Safety of Gene Therapy: New Insights to a Puzzling Case

Abstract:

Over the last few years, the transfer of therapeutic genes via gammaretro- or lentiviral vector systems has
proven its virtue as an alternative treatment for a series of genetic disorders. The number of approved phase I/II clinical
trials, especially for rare diseases, is steadily increasing, but the overall hurdles to become a broadly acceptable therapy
remain numerous. The efforts by clinicians and basic scientists have tremendously improved the knowledge available
about feasibility and biosafety of gene therapy. Nonetheless, despite the generation of a plethora of clinical and preclinical
safety data, we still lack sufficiently powerful assays to predictively assess the exact levels of toxicity that might be observed
in any given clinical gene therapy. Insertional mutagenesis is one of the major concerns when using integrating
vectors for permanent cell modification, and the occurrence of adverse events related to genotoxicity, in early gene therapy
trials, has refrained the field of gene therapy from emerging further. In this review, we provided a comprehensive
overview on the basic principles and potential co-factors concurring in the generation of adverse events reported in gene
therapy clinical trials using integrating vectors. Additionally, we summarized the available systems to assess genotoxicity
at the preclinical level and we shed light on the issues affecting the predictive value of these assays when translating their
results into the clinical arena. In the last section of the review we briefly touched on the future trends and how they could
increase the safety of gene therapy employing integrating vector technology to take it to the next level.

Abstract:Over the last few years, the transfer of therapeutic genes via gammaretro- or lentiviral vector systems has
proven its virtue as an alternative treatment for a series of genetic disorders. The number of approved phase I/II clinical
trials, especially for rare diseases, is steadily increasing, but the overall hurdles to become a broadly acceptable therapy
remain numerous. The efforts by clinicians and basic scientists have tremendously improved the knowledge available
about feasibility and biosafety of gene therapy. Nonetheless, despite the generation of a plethora of clinical and preclinical
safety data, we still lack sufficiently powerful assays to predictively assess the exact levels of toxicity that might be observed
in any given clinical gene therapy. Insertional mutagenesis is one of the major concerns when using integrating
vectors for permanent cell modification, and the occurrence of adverse events related to genotoxicity, in early gene therapy
trials, has refrained the field of gene therapy from emerging further. In this review, we provided a comprehensive
overview on the basic principles and potential co-factors concurring in the generation of adverse events reported in gene
therapy clinical trials using integrating vectors. Additionally, we summarized the available systems to assess genotoxicity
at the preclinical level and we shed light on the issues affecting the predictive value of these assays when translating their
results into the clinical arena. In the last section of the review we briefly touched on the future trends and how they could
increase the safety of gene therapy employing integrating vector technology to take it to the next level.